Relationship of Cytokines to Cognitive Functions in HCV

描述（由申请人提供）：候选人是委员会认证的临床神经心理学家，具有研究慢性丙型肝炎患者认知功能的研究经验。研究环境包括充足的办公室和实验室空间，计算机和测试设备，行政和技术人员，以及强有力的机构支持，至少将75%的时间用于开展以患者为导向的研究的职业发展。本申请的目的是为候选人提供必要的病毒神经免疫学培训，使其成为一名能够研究免疫反应和认知功能之间关系的独立研究人员。职业发展将包括病毒神经免疫学和与细胞因子测量相关的研究方法的教学和“实践”培训。候选人的长期目标是发展一个程序化的研究路线，这将有助于对免疫系统如何影响认知功能的有限理解。该项目的具体目标是：1)验证高水平的促炎细胞因子干扰素- α （IFN-a)与慢性丙型肝炎感染（CMC）患者认知功能障碍相关的假设（通过神经心理学测试测量）；2）验证高水平的干扰素- α (IFN-a)与认知功能障碍相关的假设（通过图像引导测量CMC患者复杂运动通路的抑制）。机器人定位经颅磁刺激表面肌电图（irTMS-sEMG）。CMC感染与显著的发病率和死亡率相关，包括情绪和认知障碍。更复杂的是，IFN-a， CHC的主要治疗药物，也与情绪和认知障碍有关。虽然许多研究都集中在与IFN-a治疗相关的情绪障碍上，但对相关认知困难的关注要少得多。在本研究中，CHC患者将在开始IFN-a治疗的1个月内进行神经心理测试、精神评估、细胞因子测量和irTMS-sEMG，并在IFN-a治疗12周后再次进行测试。随着时间的推移，认知功能的变化将与在同一时间间隔内接受测试的健康对照组进行比较。血清中IFN-a和其他细胞因子的水平也将被检查，并与认知功能有关。通过检查这些关系获得的知识将增加对免疫反应如何影响CHC患者思维能力的理解，并可能为思维问题的治疗提供见解。此外，这些关系可能也适用于患有其他影响思维的慢性疾病的患者，如阿尔茨海默病和系统性红斑狼疮，从而为这些患者提供可能的治疗方法。

DESCRIPTION (provided by applicant): The candidate is a board certified clinical neuropsychologist with prior research experience examining cognitive functioning of patients with chronic hepatitis C. The research environment includes ample office and laboratory space, computers and testing equipment, administrative and technical personnel, and strong institutional support for devoting at least 75% time to career development in conducting patient-oriented research. The purpose of this application is to provide the candidate with the necessary training in viral neuroimmunology to become an independent researcher capable of investigating the relationship between the immune response and cognitive functioning. Career development will include both didactic and "hands on" training in viral neuroimmunology and research methodology associated with measurement of cytokines. The long-term goal is for the candidate to develop a programmatic line of research that will contribute to the limited understanding of how the immune system influences cognitive functioning. Specific Aims of this project are: 1) to test the hypothesis that higher levels of interferon-alpha (IFN-a), a proinflammatory cytokine, are associated with cognitive dysfunction in patients with chronic hepatitis C infection (CMC) as measured by neuropsychological tests, and 2) to test the hypothesis that higher levels of IFN-a are associated with cognitive dysfunction as indicated by inhibition of complex motor pathways in patients with CMC measured by image-guided, robotically positioned transcranial magnetic stimulation surface electromyography (irTMS-sEMG). CMC infection is associated with significant morbidity and mortality, including mood and cognitive disturbances. To complicate matters further, IFN-a, the primary treatment for CHC, also is associated with mood and cognitive disturbances. While much research has focused on mood disturbances associated with IFN-a therapy, far less attention has been paid to associated cognitive difficulties. In this study, patients with CHC will undergo neuropsychological testing, psychiatric assessment, cytokine measurement, and irTMS-sEMG within 1 month of beginning IFN-a therapy and again after 12 weeks of IFN-a therapy. Changes in cognitive functioning over time will be compared to that of a healthy comparison group tested over the same time interval. Levels of IFN-a and other cytokines in serum also will be examined and related to cognitive functioning. Knowledge gained by examining these relationships will increase understanding of how the immune response affects thinking abilities of patients with CHC and may provide insights into treatments for thinking problems. Additionally, these relationships may be true in patients with other chronic diseases that affect thinking, such as Alzheimer's disease and systemic lupus erythematosus, leading to possible treatments for these patients, as well.